Prion diseases are caused by conversion of a normal cell-surface glycoprotein (PrP^C) into a conformationally altered isoform (PrP^Sc) that is infectious in the absence of nucleic acid. Although a great deal has been learned about PrP^Sc and its role in prion propagation, much less is known about the physiological function of PrP^C. In this review, we will summarize some of the major proposed functions for PrP^C, including protection against apoptotic and oxidative stress, cellular uptake or binding of copper ions, transmembrane signaling, formation and maintenance of synapses, and adhesion to the extracellular matrix. We will also outline how loss or subversion of the cytoprotective or neuronal survival activities of PrP^C might contribute to the pathogenesis of prion diseases, and how similar mechanisms are probably operative in other neurodegenerative disorders.